Literature citations

The role of AMPK/mTOR/S6K1 signaling axis in mediating the physiological process of exercise-induced insulin sensitization in skeletal muscle of C57BL/6 mice.

The crosstalk between mTORC1/S6K1 signaling and AMPK is emerging as a powerful and highly regulated way to gauge cellular energy and nutrient content. The aim of the current study was to determine the mechanism by which exercise training reverses lipid-induced insulin resistance and the role of AMPK/mTOR/S6K1 signaling axis in mediating this response in skeletal muscle. Our results showed that high-fat feeding resulted in decreased glucose tolerance, which was associated with decreased Akt expression and increased intramuscular triglyceride deposition in the skeletal muscle of C57BL/6 mice. Impairments in lipid metabolism were accompanied by increased total protein and phosphorylation of S6K1, SREBP-1c cleavage, and decreased AMPK phosphorylation. Exercise training reversed these impairments, resulting in improved serum lipid profiles and glucose tolerance. C2C12 myotubes were exposed to palmitate, resulting in an increased insulin-dependent Akt Ser473 phosphorylation, associated with a significant increase in the level of phosphorylation of S6K1 on T389. All these changes were reversed by activation of AMPK. Consistent with this, inhibition of AMPK by compound C induced an enhanced phosphorylation of both S6K1 and Akt, and silencing of S6K1 with siRNA showed no effect on Akt phosphorylation in both the absence and presence of palmitate cultured myotubes. In addition, compound C led to an elevated SREBP-1c cleavage but was blocked by S6K1 siRNA. In summary, exercise training inhibits SREBP-1c cleavage through AMPK/mTOR/S6K1 signaling, resulting in decreased intramyocellular lipid accumulation. Our results provide new insights into the mechanism by which AMPK/mTOR/S6K1 signaling axis mediates the physiological process of exercise-induced insulin sensitization.

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